Detailed Clinical Features and Genotype-Phenotype Correlation in an OTOF-Related Hearing Loss Cohort in Japan

Abstract OTOF is one of the most frequent causes of hereditary hearing loss and a main cause of auditory neuropathy spectrum disorder (ANSD). Although it is reported that most of the patients with OTOF mutations have stable, congenital or prelingual onset severe-to-profound hearing loss, some patients show atypical clinical phenotypes, and the genotype-phenotype correlation in the patients with OTOF mutations is not yet fully understood. In this study, we aimed to reveal detailed clinical characteristics of OTOF-related hearing loss patients and the genotype-phenotype correlation. Detailed clinical information was available for 65 patients in our database who were diagnosed with OTOF-related hearing loss. As reported previously, most of the patients (90.8%) showed a “typical” phenotype, prelingual and severe-to-profound hearing loss. Forty-seven patients (72.3%) underwent cochlear implantation surgery and showed successful outcomes; approximately 85-90% of the patients showed a hearing level of 20-39dB with cochlear implant and a CAP scale (Categories of Auditory Performance) level 6 or better. Although truncating mutations and p.R1939Q were clearly related to severe phenotype, almost half of patients with one or more non-truncating mutations showed mild-to-moderate hearing loss. Notably, patients with p.H513R, p.I1573T and p.E1910K showed “true” auditory neuropathy-like clinical characteristics. In this study, we have clarified genotype-phenotype correlation and efficacy of cochlear implantation for OTOF-related hearing loss patients in the biggest cohort studied to date. We believe that the clinical characteristics and genotype-phenotype correlation found in this study will support preoperative counseling and appropriate intervention for OTOF-related hearing loss patients.